Niclosamide suppresses gastric cancer progression through YTHDF2 inhibition-affected lactate metabolic reprogramming

Gastric cancer (GC), a highly aggressive tumor with significant mortality, exhibits metabolic reprogramming involving glucose, lipid, and amino acid metabolism. This study employed non-targeted metabolomics and transcriptomics to analyze metabolic alterations in patients with GC, complemented by single-cell RNA-seq to dissect lactate shuttle dynamics and metabolic alterations between tumor epithelial and endothelial cells. The impact of niclosamide and YTHDF2, an m6A methylation regulator, on gastric cancer cell proliferation was investigated both <i>in vitro</i> and <i>in vivo</i>. Niclosamide disrupted metabolic reprogramming and lactate dynamics within the tumor microenvironment. YTHDF2 emerged as a critical modulator of GC metabolism, with niclosamide suppressing tumors through the YTHDF2-mediated regulation of metabolic genes. Our research revealed comprehensive metabolic alterations in gastric cancer, including upregulated lactate metabolism that promotes tumorigenesis via the lactate shuttle. Niclosamide targets the m6A methylation regulatory protein YTHDF2, which influences genes related to metabolism, indicating its potential as a prospective treatment for GC.